Despite decades of research, a limiting obstacle to personalizing oncology is identifying correlates of response against a diverse genetic background. For individuals with rare subtypes of human cancers where minimal data exists, this problem is compounded. We simply MUST do better for our patients, and this application is built around the notion that new paradigms of innovative translational research must be considered. We are, therefore, proposing at a scale and scope never before possible, to use sporadic canine cancers to model rare human cancers, with dog and man both iteratively informing the other species personalized clinical trials. Veterinary scientists have found that the low genetic diversity caused by selective breeding in dogs makes it easier to identify genetic differences that can affect responses to drugs. There are significant advantages to this approach that we believe portend a high likelihood of success. First, because of selective breeding genetic variation within canine breeds is very low. Second, since each breed is derived from a small group of founders, most tracing back approximately 150 years, many of the genes associated with polygenic traits are fixed so only a few variable genes determine phenotype. This means that it will be much easier to identify genetic disease determinants in dogs than in humans. Third, dogs have a higher incidence of a number of tumors that are considered rare in humans. The ability to identify, recruit, and study cancers within a breed of dog offers new avenues of hope for research into personalized medicine and the underlying causes of rare malignancies that afflict human patients. Fourth, it is important to note that the outcomes of this project will have a broad impact in translational research not only for humans but also for dogs. The AVMA estimates that almost half of pets over 10 years of age will die from cancer and the individualization of therapy for canine patients is a stated goal of the participating Comparative Oncology Section of the NCI. Finally, this application overcomes one of the limiting aspects plaguing the field of comparative oncology, direct access to biomaterials, something solved by our industrial partner, PetSmart (who has agreed to partially match the funding for this application). For this reason, we have formed a coalition of clinicians, veterinarians, and scientists into the Canine Hereditary Cancer Coalition (CHCC) described in this application. This "bark to bedside" approach (humor intended) will molecularly inform patient trials (especially for rare malignancies). For patients with cancer, dog may again be considered man's best friend! PUBLIC HEALTH RELEVANCE: The outcomes of this project will have broad impact to both human and veterinary clinical communities. Using sporadic canine cancers to model rare human cancers, dog and man can both iteratively informing the other species personalized clinical trials has enormous potential Identifying novel therapeutic approaches for the treatment of rare human cancers like angiosarcoma, osteosarcoma, and oral melanoma, also identifying novel therapies for the treatment of common canine cancers.